The continuing of this long-standing and very successful HD Center is the investigation of the HD pathogenic process, beginning at its starting point, the genetic defect and proceeding to its inevitable clinical and neuropathological consequences. Our ultimate goal is to develop the knowledge necessary to design an effective rational therapy for HD. As we have in the past, HD Center investigators continue to approach the problem from several different points of view, creating a synergistic energy that has fostered great advances in this field. In past grant cycles, we mapped the HD defect, identified it as a CAG repeat expansion, discovered huntingtin aggregates as a new pathologic correlate and developed genotype-phenotype correlations to guide further investigations. In this renewal cycle, we will build on this and other advances to proceed down the disease pathway. Project 1 (Gusella): Toxicity and Specificity Components of HD Pathogenesis will use biochemical approaches to investigate the novel physical property conferred on huntingtin by the expanded glutamine tract and its consequences for the protein in HD brain as well as to explore methods of interfering with its effects. It will also establish Drosophila as a genetic system for exploring huntingtin's normal function. Project 2 (Myers): HD Genetic and Neurobiological Studies will focus on identification of genetic modifiers of HD pathogenesis which could provide an alternative approach that could lead to a treatment. Project 3 (MacDonald): Intermediates in HD Pathogenesis will take advantage of HD animal models to assess the potential for huntingtin interactors to be involved in triggering HD pathogenesis and the basis for striatal specificity of the disorder. Project 4 (DiFiglia): Early subcellular and Molecular Pathology will utilize cell biological approaches to investigate the generation of huntingtin fragments, as well as exploring potential involvement of nuclear or cytoskeletal dysfunction, apoptotic pathways and microglial activation in HD pathogenesis. There projects will be supported by cores for Administration (Gesella), Neuropathology (Vonsattel), Genotyping (MacDonald) and Imaging (DiFiglia). Collectively these studies represent a concerted effort to understand and treat HD and promise to continue the rapid rate of progress achieved by this HD Center.